Pharmacological manipulation of fracture healing and bone ...

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LUND UNIVERSITY

PO Box 117221 00 Lund+46 46-222 00 00

Pharmacological manipulation of fracture healing and bone remodeling

Harding, Anna Kajsa

2010

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Citation for published version (APA):Harding, A. K. (2010). Pharmacological manipulation of fracture healing and bone remodeling. Department ofOrthopaedics, Lund University.

Total number of authors:1

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Bone 46 (2010) 649–654

Contents lists available at ScienceDirect

Bone

j ourna l homepage: www.e lsev ie r.com/ locate /bone

A single dose zoledronic acid enhances pin fixation in high tibial osteotomy using thehemicallotasis technique. A double-blind placebo controlled randomized study in46 patients

Anna Kajsa Harding a,⁎, Sören Toksvig-Larsen b, Magnus Tägil a, Annette W-Dahl a

a Department of Orthopedics, Clinical Sciences Lund University and Lund University Hospital, SE-221 85 Lund, Swedenb Department of Orthopedics, Hässleholm Hospital, Hässleholm, Sweden

⁎ Corresponding author.E-mail address: [email protected] (A.K.

8756-3282/$ – see front matter © 2009 Elsevier Inc. Adoi:10.1016/j.bone.2009.10.040

a b s t r a c t

a r t i c l e i n f o

Article history:

Received 21 September 2009Revised 30 October 2009Accepted 30 October 2009Available online 11 November 2009

Edited by: T. Einhorn

Keywords:Pin fixationZoledronic acidExternal fixatorTibial osteotomyOsteoarthrit

Introduction: Bisphosphonates have been shown to reduce osteoclastic activity and enhance pin fixation inboth experimental and clinical studies. In this prospective, randomized study of high tibial osteotomy usingthe hemicallotasis (HCO) technique, we evaluate whether treatment by one single infusion of zoledronic acidcan enhance the pin fixation.Materials and methods: 46 consecutive patients (35–65 years) were operated on for knee osteoarthritis bythe HCO technique. After the osteotomy, two hydroxyapatite-coated pins were inserted in the metaphysealbone and two non-coated pins in the diaphyseal bone. The insertion torque was measured by a torque forcescrew driver. Four weeks postoperatively, the patients were randomized to either one infusion of zoledronicacid or sodium chloride intravenously. At time for removal of the pins, the extraction torque forces of thepins were measured.Results: All osteotomies healed and no difference was found in time to healing. The mean extraction torqueforce in the non-coated pins in the diaphyseal bone was doubled in the zoledronic treated group (4.5 Nm, SD2.1) compared to the placebo group (2.4 (SD 1.0, pb0.0001). The mean extraction torque forces of the

hydroxyapatite-coated pins in the metaphyseal bone were similar in the zoledronic acid group (4.7 Nm, SD1.3) and in the placebo group (4.0 Nm, SD 1.3).Discussion: A single infusion of zoledronic acid improved twofold the fixation of non-coated pins indiaphyseal bone. Bisphosphonates might be an alternative to hydroxyapatite-coated pins in nonosteoporoticbone.

© 2009 Elsevier Inc. All rights reserved.

Introduction

A stabile pin fixation is a prerequisite during treatment by externalfixation to minimize the risk of complications such as pin loosening,delayed healing, non-union and pin site infection [1]. Various pin andscrew designs have been compared to optimize the thread and tipdesign in order to enhance the fixation [2-4]. In several, both animaland clinical studies, improved fixation and reduced rates of pin siteinfection have been described with the use of hydroxyapatite (HA)-coated pins in both cancellous and cortical bone [1,5-7]. A novelapproach to influence the bone–pin interface is to delay the boneresorption around the pins and maybe prevent early loosening bysystemic administration of a bisphosphonate [8-12].

Bisphosphonates have been shown to reduce the osteoclasticcatabolic activity in experimental studies, not only in osteoporosis butalso in other orthopaedic indications, such as osteonecrosis [13,14] ,

Harding).

ll rights reserved.

fracture healing [15,16] and prosthetic fixation [17,18]. Bispho-sphonates bind to the bone mineral and when the bone is resorbedby the osteoclasts, bisphosphonates are released and internalized bythe osteoclast. This leads to apoptosis of the osteoclast by interferencewith the cell metabolism [19] and resorption is delayed. By reducingthe resorption of the bone surrounding an implant, theoretically anincreased fixation can be achieved. Bisphosphonate treatment of thebone adjacent to a screw has been shown mechanically effective inpull-out tests of screws experimentally. Both by local and systemicaltreatment, an enhanced extraction torque was found by 56% and forpull-out strength between 15-30% [8]. Also for HA-coated [20] orporous implants [21] the osseointegration was accelerated byadministration of bisphosphonates.

The first randomized clinical study in humans showed that weeklyadministration of alendronate improved pin fixation in cancellousbone but not in cortical bone in osteoporotic elderly female hipfracture patients treated with external fixation [10]. In the presentstudy, which was designed primarily to decrease the time to fracturehealing by delaying the resorption of the forming callus, a delayeddistribution of the bisphosphonate was chosen, which has been

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shown to be more effective in fracture healing in animal studies [22].For pin fixation, an immediate or even pre-treatment would havebeen theoretically better.

High tibial osteotomy by the hemicallotasis technique (HCO) is atreatment option for younger and/or physically active patients withunicompartmental knee osteoarthritis or knee deformities. HCO is anopen wedge technique, based on an external fixation, and both HA-coated and -uncoated pins are used [23]. The angle deformity issuccessively corrected postoperatively under radiographic control.The advantages of the HCO include an easy surgical technique andimproved possibility to achieve the planned correction. HCO is also aprocedure with high demands on pin fixation, due to early weightbearing combinedwith forces necessary for the angular correction. Allthis makes the HCO an appropriate and repeatable clinical model forstudying bone and fracture healing including pin fixation, and toinvestigate the effect of a bisphosphonate.

During a pilot-study of bisphosphonate treatment on bone healingin patients operated on by the HCO [24], it was noted that theextraction torque of the non-coated pins in the diaphyseal bone washigher in those treatedwith bisphosphonate compared to non-treatedpatients. In the present full size randomized study, with fracturehealing as primary outcome, our secondary aim was to evaluate iftreatment by a single infusion of 4 mg zoledronic acid intravenouslyaffected the pin fixation during the HCO.

Materials and methods

Between February 2006 and May 2007, 46 consecutive patients(10women and 36men)with amedian age of 50 years (range 37–63)(Table 1) were operated on by HCO. Patients between 35 and 65 yearswith osteoarthritis or deformities of the knee were included andexclusion criteria were kidney, liver or odontological disorders,rheumatoid arthritis or bisphosphonate treatment during the 2-yearperiod prior to the operation. Preoperatively, the patients were givenboth written and verbal study information and an informed consentwas obtained. The study was approved by the local ethics committeeat Lund University as well as the SwedishMedical Product Agency andthe study was externally monitored. The study was registered at theEuropean Community data base EudraCT with the number 2005-002985-12. All patients that met the inclusion criteria wereprescribed daily oral calcium and vitamin-D3 the first 6 weekspostoperatively to avoid hypocalcaemia if given the active drug. Theflow of the participants through each stage of the trial is outlined in aflow diagram (Fig. 1).

Surgery and randomization

The HCO was performed as an out-patient procedure using theOrthofix® T-garche as external fixator (Fig. 2). The two proximalholes in the metaphyseal bone were made with a 3.2-mm drill andthe distal holes in cortical bone with a 4.8-mm drill. Four conicalstainless steel pins were inserted (6/5-mm diameter), whereof two

Table 1Patient characteristics.

Zoledronate, n=25 Control, n=21

Men/women 19:6 17:4Age (years)a 49 (37–63) 50 (42–61)Pre-HKA(degrees)b 173±6 173±5BMI (kg/m2)b 28±3 26±3Smoker 4 7Smokeless tobacco user 4 6

HKA=Hip-knee-ankle angle (b180 degrees=varus).BMI=Body Mass Index.

a The value given as median and range.b The value given as the mean and the standard deviation.

hydroxyapatite (HA)-coated (Orthofix® Bussolengo, Italy) in themetaphyseal bone and two un-coated pins in the diaphyseal bone(Orthofix®). The HA coating was applied by plasma spraying, withan HA-layer thickness of 45–70 μm [23]. The pins must penetratethe posterior cortex with 2–3 threads for best fixation, which wascontrolled in fluoroscopy. A 5-cm longitudinal skin incision wasdone ventral to the tibial tuberosity. The osteotomy was done at thelevel of the distal third of the tibial tuberosity. The osteotomy wastested and judged to be sufficient if the gap could easily be opened4–5 mm. For valgus deformity, the surgical procedure was identicalexcept that a fibulotomy was performed 10–15 cm below the headof the fibula [23]. The patients were allowed free mobilization andfull weight bearing after the operation. No prophylactic antibioticwas used. Pin site care was carried out once a week usingchlorhexidine moistened gauzes as dressings in the orthopaedicoutpatient clinic. In case of pin site infections oral antibiotictreatment (flucloxacillin 1 g×3) was given for 7 days.

At 4 weeks postoperatively, inclusion and exclusion criteriawere re-evaluated and randomization was performed by one of theauthors (AWD) using closed envelopes. The patient received eitheran infusion of zoledronic acid 4 mg (Zometa®, Novartis PharmaGmbH, Basel, Switzerland) or sodium chloride 9 mg/ml preparedby the unblinded nurse. The infusion of zoledronic acid wasprepared by diluting 4 mg zoledronic acid in 100 ml sodiumchloride 9 mg/ml and was given as a 15-min intravenous infusion.If a patient had signs of hypocalcaemia at the follow up, the serumcalcium was measured.

Outcome

Both the insertion and extraction torque forces (Nm) of the pinswere measured using a torque force screwdriver (range 0-1100 Ncm;Orthofix® SRL, Italy). The torque screw pin driver was set to zerobefore starting. One torque force screwdriver was available at theoperating theatre and another in the outpatient clinic. The pins wereinserted by the surgeon in a slow clockwise turn. The torque wasmeasured during the whole insertion procedure and the peak torquewas registered as the pin engaged the second cortex. The extractionwas done in a slow counter clockwise turn and the maximum peaktorque recorded immediately as the screw loosened. The decision toremove the fixator was made by the treating surgeon (STL), who wasblinded to the type of infusion given at 4 weeks and to any side effectsof the drugs experienced by the patient. The decision was based on acombination of radiological and ultrasound examination of theosteotomy healing and a weight-bearing test—i.e. walking, for acouple of hours to days, without the fixator but with the pins still insitu [25]. If the patient reported symptoms of incomplete healing,mainly pain by loading, the fixator was reapplied for additional2 weeks. This procedure was repeated every second week until theosteotomy healing was clinically satisfying. The pins were removed inthe out-patient clinic.

The pin performance index (PPI) was used as primary outcomeand was calculated from the insertion and extraction torque. PPI isthe ratio of extraction to insertion torque and expressed aspercentage [26]. An equal insertion and extraction torque wouldresult in a PPI of 100%. The PPI gives the information of how thefixation proceeds over time. The need (number of patients) and use(days/treated patient) of antibiotics were used as outcomes of pinsite infection. All drug-related side-effects and adverse events wereregistered prospectively during the study. Complications such asdelayed healing (by definitionN16 weeks in external fixation [25]),non-union, septic arthritis, deep venous thrombosis, loss ofcorrection and others (including replacement of pins and difficultiesof correction) were recorded. At 10 weeks postoperatively dualenergy X-ray absorptiometry (DEXA) of the operated lower leg andbilateral proximal femur was performed. The total T-score of the

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Fig. 1. A Consolidated Standards of Reporting Trials (CONSORT) flow diagram depicting patient recruitment, randomization, patient flow, and follow-up in the study.

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proximal femur was used to evaluate if the patients hadosteoporosis, osteopenia or normal bone.

Statistical methods

A power analysis was performed based on the data from the pilotstudy as well as previous pin design studies. 25 samples were neededin each group to obtain a power of 85% at p=0.05 in a two-sided test,with an estimated mean difference of insertion and extraction torqueforce of 1.00 Nm (SD 1.5) between the bisphosphonate and controlgroup. For each patient the mean value of the two proximal pins andthe mean value of the two distal pins were calculated and used for thestatistical analysis. For bilateral procedures, the index operation wasused for statistical analysis.

All data were expressed as the mean and standard deviation of themean. For Pin Performance Index (PPI), the mean difference and 95%CI of the difference was calculated. Independent samples t test wasperformed to test the differences between the groups. pb0.05 wasconsidered statistically significant. Statistical analysis was carried outwith the Statistical Package for the Social Sciences (SPSS) Software(version 16.0; SPSS, Chicago, Illinois).

Source of funding

Funding was received from hospital and government researchfunds. The study was carried out independently from manufacturersof used pharmaceuticals and devices.

Results

In both groups all osteotomies healed and there was no delayedhealing or non union in either of the groups. The healing time was 77(SD 7) days in the zoledronic group and 77 (SD 7) days in the placebogroup (NS). No patients had signs of hypocalcemia. None of thepatients had osteoporosis but three patients in the zoledronic treatedgroup had osteopenia and six in the control group. Six patientsunderwent bilateral procedures, four were in the zoledronate groupand two in the placebo group.

HA-coated pins

In the proximal HA-coated pins in the metaphyseal bone,zoledronic acid did not significantly increase the PPI (Table 2). The

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Fig. 2. Hemicallotasis osteotomy using the Orthofix® T-garche as external fixator (A). Antero-posterior (B) and lateral (C) radiographs.

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insertion torque force for the HA-coated proximal pins inmetaphysealbone was 2.0 Nm (SD 0.6) for the zoledronic group and 1.5 Nm (SD0.6) for the placebo groups (p=0.02). The extraction torque force was4.7 Nm (SD 1.3) in the zoledronic group and 4.0 Nm (SD 1.3) in theplacebo group (p=0.12) and the ratio expressed as PPI for theproximal HA-coated pins was 257% (SD106) in the zoledronic groupand 289% (SD 115) in the placebo group, mean difference -27 (95%CI101 to 37, p=0.4). 9 proximal pins in 5 patients were excluded (5 inthe zoledronic group and 4 in the control group) due to missedmeasurement at time for insertion and/or extraction. In two patients(one in the zoledronic group, one in the control group) the insertiontorque force of both pins was not measured and in two patients (onein the zoledronic group, one in the control group) the extractiontorque force of both pins was not measured. We did not exclude thesepatients in the calculation of the insertion and extraction torqueforces respectively but it was not possible to calculate PPI. In onepatient (zoledronic group) the insertion torque force of themedial pinwas not measured. For this patient the PPI was calculated using themeasurement of the lateral pin.

Standard pins

In the standard distal pins in the diaphyseal bone there was adifference between the bisphosphonate treated group and thecontrols (Table 2). The insertion torque force for the distal standard

Table 2Insertion/Extraction Torque and Pin Performance Index (PPI) in metaphyseal anddiaphyseal bone.

Zoledronate, n=25 Control, n=21 p value

Metaphyseal bonePin Insertion Torque (Nm) 2.0±0.6 1.5±0.6 0.02Pin Extraction Torque (Nm) 4.7±1.3 4.0±1.3 NSa

PPI (%) 257±106 289±115 NSa

Diaphyseal bonePin Insertion Torque (Nm) 7.0±2.0 7.0±1.7 NSa

Pin Extraction Torque(Nm) 4.5±2.1 2.4±1.0 b0.0001PPI (%) 62±23 35±14 b0.0001

The values given as the mean and the standard deviation.a NS=not significant.

pins in the diaphyseal bone was 7.0 Nm (SD 2.0) for the zoledronicacid group and 7.0 Nm (SD 1.7) for the placebo group (p=0.9). Theextraction torque force was higher in the zoledronic acid group 4.5Nm (SD 2.1) than in the control group 2.4 Nm (SD 1.0) (pb0.0001)and the corresponding PPI for the standard pins in the diaphysealbone was 62% (SD 22.9) in the zoledronic group compared to the 35%(SD 14.3) in the placebo group, mean difference 27 (95%CI 15 to 39,pb0.0001). 6 distal pins in 3 patients were excluded (2 in thezoledronic group and 4 in the control group) due to missedmeasurement at time of insertion and/or extraction. In two patients(one in the zoledronic group, one in the control group) the insertiontorque force of both pins was not measured and in one patient(control group) the extraction torque force of both pins was notmeasured. We did not exclude these patients in the calculation ofinsertion and extraction torque force respectively, but it was notpossible to calculate PPI.

Pin site infection and complications

There was no difference in pin site infections between the twogroups evaluated as the need and use of antibiotics. 5/25 patients inthe zoledronic group had antibiotic treatment during the time inexternal fixation compared to 7/21 in the placebo group RR 0.6 (95%CI 0.23 to 1.57, p=0.33). The use of antibiotics per treated patientwas 8 (SD 3) days in the zoledronic group and 11 (SD 5.5) days in theplacebo group (p=0.4). No differences were found regardingcomplications between the groups. One DVT was observed in thecontrol group. 13/25 patients reported muscle pain and flu symptomsin the zoledronic group compared to 2/21 in the placebo group (RR5.04, 95% CI 1.3 to 20, p=0.004). One serious adverse event wasregistered in the zoledronic group in form of chest pain due topneumonia.

Discussion

HA coating of pins for external fixation has been developed andproven effective to increase the fixation in both cancellous andcortical bone in HCO [1,5]. In some situations the HA-coating by itselfseems to be of more importance than the pin design [7] but the effectdiffers greatly between cancellous and cortical bone. In lengthening

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procedures where the implantation time and themechanical loads aresubstantial, the HA-coated pins were superior to uncoated pins withextraction torques being almost 90 times higher [27]. In our clinicalmodel the pin fixation is satisfactory with HA-coated pins in themetaphyseal bone and standard pins in the diaphyseal. HA-coatedpins in the diaphyseal bone can be too well fixed and thereby painfuland difficult to remove in the out patient clinic [6]. However, in othersituations, HA-coated pins may be necessary depending of the qualityof the bone, the length of the treatment and the increased forcesdepending on the type of treatment. In these situations bispho-sphonate treatment, whether systemically or locally applied, might bean alternative in the future but more studies have to be made to findthe optimum dose, timing and mode of application.

High tibial osteotomy by HCO is a clinical fracture model whereboth HA-coated and standard pins are used andwith high demands onpin fixation due to early weight bearing combined with large forces atthe angular correction [5]. A high load is carried by the pins and thecontact pressure at the interface between pin and bone might be highenough to induce resorption around the pin, especially during thehemicallotasis procedure/correction phase, and could lead to pinloosening.

The use of bisphosphonates in orthopaedic conditions other thanosteoporosis and bone metastasis is limited but increasing and thedrug has been used also to improve the fixation of orthopaedic pins.Bisphosphonates are effective in increasing the fixation measured asthe extraction torque, both in animal models [8] as well as in humanseries [10]. Delaying the hypothetical resorption around the pins dueto such pressure induced resorption, micro cracks [28] or thermalinjury [29], bisphosphonate treatment appears attractive to improvepin fixation during fracture healing, especially since animal studiesimplicate a positive effect on fracture healing due to a better retentionof the new formed callus [16].

In the present study, we could show an improved fixation, inpatients operated on by the HCO and treated with a single dose ofzoledronic acid, of the non-coated pins in the cortical diaphyseal bonedistally but not of the HA-coated pins in the cancellous metaphysealbone proximally. In a previous study using the same technique,uncoated proximal standard pins in cancellous bone all became loosein contrast to the HA-coated [5], which is why HA pins are usedproximally in the clinical practice. In the same study, no suchloosening was found in the diaphysis in either group, but the standardpins lost about 40% of their fixation during the fixation time, incontrast to the HA-coated pins, which increased the fixation/insertiontorque. In the present study, only using standard pins distally in thecortical bone, an increase by 88% was found in the zoledronic acidgroup compared to the placebo, an effect similar to the HA coatingfound previously.

In a recently published, randomized study, bisphosphonatesincreased the fixation also in HA pins [10]. Hip fractures were fixatedwith twoHA-coated pins in the femoral neck aswell as twoHA-coatedpins in the femoral shaft. The patients were given weekly peroralalendronate for 3 months. An almost doubled extraction torque wasfound in the bisphosphonate-treated group in the cancellous but notin the cortical bone. Several explanations can be discussed to thesediverging findings compared to our study. In the present study, thepatients are osteoarthritic and younger (50 years, range 37–69) thanthe hip fracture patients (83 and 86 years±4–7) and thus the degreeof osteoporosis substantially less. The pin fixation therefore might bebetter already at insertion and the insertion torques are higher in thepresent study of osteoarthritis patients than in the hip fracturepatients. In hip fracture fixation, the pins in the femoral head arerelying on cancellous bone fixation only, whereas in the knee eachcancellous pin still has a bicortical grip. Further, in the present study,the bisphosphonate was given as a single injection intravenously after4 weeks compared to weekly peroral distribution for 3 monthsstarting the first week after surgery in the Moroni study. The effect of

the bisphosphonate would hypothetically be better if given initially,delaying the resorption of any bone necrosis in the pin holes causedby the surgical trauma. The rationale for single delayed injection inour studywas based on animal experiments in regard to healing of theosteotomy. In fracture healing, a superior effect has been found with adelayed administration compared to administration immediatelyafter the fracture. Bisphosphonates are taken up by the callus at thetime of distribution and has greater effect on the strength with adelayed distribution as the callus has started to form [22]. Using asingle dose and a delayed dosing also decreased the risk of interferingtoo early with the bone formation and fracture healing. However, if anincreased pin fixation is the target, the bisphosphonate should beadministered immediately to avoid the early resorption around thepins due to heat or mechanical necrosis.

Pin fixation is associated to pin site infection and a loose pin maylead to a pin site infection aswell as a pin site infectionmay lead to pinloosening. HA coating of external fixation pins increases the stabilityand thereby reduces the risk of pin site infection [30]. In a previousstudy comparing infected to un-infected pin sites at removal, nodifferences were found in pin extraction torque force with HA-coatedpins, whereas in the standard pin group there was a significant lowerextraction torque force in pins classified as infected pin sites than inun-infected [1]. However, the amount of clinically relevant infectionsin that study was lowwith only 4 clinically relevant grade 2 infectionsaccording to the Checkett–Otterburns classification [31] in thestandard pin group and none in the HA-coated pin group. In thepresent study, the need (33% of the patients) and use (11 days/treated patient) of antibiotics during the time in external fixationwere the same in the control group as in our prior studies [32,33].There was no statistically significant difference in extraction torqueforce between patients treated with antibiotics or not treated, duringthe time in the external fixator.

Finally, the price of the drug must be considered and cheaperperoral alternatives exist. In the present study a single injection waschosen to ensure full compliance in the clinical trial situation.Further, the patients in the zoledronate treated group reportedmuscle pain and flu symptoms significantly more than in the controlgroup. These symptoms are known side effects of the intravenouslyadministered bisphosphonates and can be avoided using peroraladministration. The long term side effects of bisphosphonates arearising in patients treated for years and will hardly appear in asingle-dose or short-term regimen. Further studies are thusnecessary to investigate mode of administration, dosing, frequencyand whether it is possible to treat the bone locally, either by coatingthe pin itself or by implanting the bisphosphonate in the drill hole[8,11,12] before bisphosphonates are recommended in additionwhen using an external fixator.

In conclusion, an almost 100% improved pin fixation was found inthe uncoated pin in diaphyseal bone whereas no effect was found inthe HA-coated pin in metaphyseal bone. Maybe bisphosphonatetreatment, systemically or preferably locally, can be an alternativewhen non-coated pins are used but in our model a bisphosphonatedoes not seem to improve fixation additionally compared to HAcoating alone.

Acknowledgments

The project was supported by Region Skåne, Lund UniversityHospital, the Swedish Medical Research Council (project 09509),Thure Carlsson, Alfred Österlund, Greta and Johan Kock and MaggieStephens foundations and the Faculty of Medicine, Lund University.

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